L-ARGININE PREVENTS CYCLOSPORINE-A - INDUCED PULMONARY VASCULAR DYSFUNCTION

Background. Cyclosporin A is known to alter endothelium-dependent resp onses to different agonists. Few data are available concerning the eff ect of cyclosporin A on the pulmonary vascular bed. Methods. The endot helium-dependent responses to acetylcholine (20 mu g), bradykinin (5 m u g), and substance P (5 mu g) were investigated in a dog model of lef t lung autoperfusion at constant flow. Results. The vasodilator respon se to bradykinin and substance P was significantly decreased with cycl osporin A (20 mg) administration. The average decreases in pulmonary a rterial pressure with bradykinin were 5.4 +/- 1.5 mm Hg and 2.4 +/- 0. 4 mm Hg before and after cyclosporin A administration, respectively (p = 0.04). The average decreases in pulmonary arterial pressure with su bstance P were 4.4 +/- 1.0 mm Hg and 1.8 +/- 0.5 mm Hg before and afte r cyclosporin A administration, respectively (p = 0.04). The responses to acetylcholine and the endothelium-independent relaxing agent nitro glycerin were not significantly affected by cyclosporin A. The effects of cyclosporin A on endothelium-dependent responses to bradykinin and substance P were overcome nously). The decreased response to bradykin in and substance P after cyclosporin A administration was not signific antly affected by indomethacin, a cyclooxygenase inhibitor. The pulmon ary angiotensin-converting enzyme activity was also measured using [H- 3]benzoyl-phenylalanyl-glycyl-proline, an inactive angiotensin-convert ing enzyme substrate. There was an average [H-3]benzoyl-phenylalanyl-g lycyl-proline hydrolysis of 54% +/- 2% and 55% +/- 2% before and after cyclosporin A administration, respectively (not significant). Conclus ions. The present study suggests that cyclosporin A selectively decrea ses endothelium-dependent responses to bradykinin and substance P with out affecting the cyclic guanosine monophosphate-dependent pathway in the canine pulmonary vascular bed. The decreased endothelium-dependent responses to bradykinin and substance P are not related to increased angiotensin-converting enzyme activity. The toxic effect of cyclospori n A on endothelium-dependent responses is reversible by the administra tion of L-arginine, a source of substrate for nitric oxide. (C) 1997 b y The Society of Thoracic Surgeons.